Özet:
Understanding the genetic basis of hereditary diseases elucidates the molecular mechanisms underlying disease manifestations and uncovers valuable information about gene function. Consanguineous families are very useful for mapping hereditary disease loci. In addition, recent advances in the technologies of genotyping arrays and next generation sequencing as well as their decreasing costs made disease gene search easier. In this thesis, three families afflicted with different recessive hereditary diseases, autosomal recessive ataxia, azoospermia and progressive myoclonic epilepsy with dystonia (PMED), were studied. Ataxia is a neurological disorder, mainly characterized by lack of coordination in muscle movements. A consanguineous family with two brothers afflicted by ataxia, associated with spasticity, leukodystrophy, oculomotor apraxia and hearing loss, was studied. Four candidate loci were found, novel variants at the loci were investigated via exome sequencing, and the disease gene was identified at 3q21.1-22.1. Azoospermia is the condition in males where there is no detectable spermatozoon in the semen. Two candidate loci at 4p16.2-p16.1 and 18q12.1 were found, the loci were examined via exome sequencing, and the disease gene was identified at 18q12.1. PMED is a novel form of progressive myoclonic epilepsy, similar to FIME (MIM 605021) but with a much more severe clinical course. The disease locus is at 16pter-p13.3. A 2-bp deletion in exon 3 of TBC1D24, c.969_970delGT (p.S324TfsX3), was identified. The mutation resulted in frameshift and was predicted to lead to a premature termination codon. The mutation was predicted to affect only one isoform and relative expression of different isoforms was assessed in seven different human brain regions. Meanwhile, two novel transcript isoforms, both harboring exon 3, were identified.
